Modeling of Hyperparathyroidism-Jaw Tumor Syndrome by Targeted Deletion of Hrpt2

描述（由申请人提供）：甲状旁腺功能亢进颌骨肿瘤综合征（HPT-JT）是一种综合征，使个体易患一种或多种良性或恶性甲状旁腺肿瘤、下颌骨和/或上颌骨骨化纤维瘤、良性或恶性子宫肿瘤，以及较少见的囊性肾病变、肾错构瘤或威尔姆氏瘤。受影响的个体可能在其一生中发展多发性原发性甲状旁腺、颌骨、子宫和/或肾脏肿瘤。编码parafibromin的hrpt2肿瘤抑制基因（也称为CDC73）失活突变被确定为大多数受影响种类中HPT-JT的遗传原因。随后，散发性甲状旁腺癌、下颌骨骨化纤维瘤和肾脏肿瘤的筛查显示HRPT2的种系和体细胞突变。在完整动物的病理生理学相关实验背景下，拟议的研究旨在解决Hrpt2/parafibromin缺失促进甲状旁腺和颌骨肿瘤形成的机制。为了在体外研究Hrpt2基因敲除的病理生理后果，我们培育了Hrpt2基因两侧有两个loxP位点的基因工程小鼠，并将其与两种不同的转基因小鼠品系PTH-Cre和Wnt1-Cre杂交。这些杂交将导致在甲状旁腺或下颌骨分别有Hrpt2缺失的后代。这两种小鼠模型的建立将为解剖HPT-JT、散发性甲状旁腺瘤和骨化性颌骨纤维瘤的分子基础提供手段，并可能最终促进新的诊断和治疗策略的发展。

DESCRIPTION (provided by applicant): Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is a syndrome that predisposes individuals to the development of one or more benign or malignant parathyroid tumors, ossifying fibromas of the mandible and/or maxilla, benign or malignant uterine tumors and, less commonly, cystic kidney lesions, renal hamartomas or Wilm's tumors. Affected individuals may develop multiple primary parathyroid, jaw, uterine and/or kidney tumors over the course of their lifetime. Inactivating mutations of theHRPT2 tumor suppressor gene (also called CDC73), encoding parafibromin, were identified as the genetic cause of HPT-JT in the majority of affected kindreds. Subsequently, screens of sporadic parathyroid carcinomas, ossifying fibromas of the mandible and renal tumors revealed both germline and somatic mutations of HRPT2. The proposed studies are designed to address the mechanisms through which loss of Hrpt2/parafibromin promotes neoplasia in the parathyroid glands and jaws, in the pathophysiologically relevant experimental context of an intact animal. To study the pathophysiological consequences of knockout of Hrpt2 in vitro, genetically- engineered mice in which the Hrpt2 gene is flanked by two loxP sites have been generated and will be crossed with two different transgenic mouse strains, PTH-Cre and Wnt1-Cre. These crosses will result in offspring with Hrpt2 deletion in the parathyroid glands or mandible, respectively. Development of these two mouse models will provide a means for dissecting the molecular basis of HPT-JT, sporadic parathyroid tumors and ossifying jaw fibromas and may ultimately enable the development of new diagnostic and treatment strategies.